Inflammatory bowel diseases (IBD) are autoimmune disorders characterized by considerable heterogeneity in their clinical manifestations. These complex entities are grouped mainly into ulcerative colitis (UC) and Crohn’s disease (CD). These diseases are marked by dysregulated interactions between the mucosal immune system and the epithelial barrier, leading to conditions such as intestinal dysbiosis. In this pathological context, γδ (γδ) T-cells play a crucial role in maintaining intestinal epithelial homeostasis (Li et al., 2023).

γδ T-cells represent a non-conventional subset of T lymphocytes, distinguished by their unique T-cell receptor (TCR) composed of γ and δ chains. In contrast to the more prevalent αβ T-cells, γδ T-cells act as a bridge between innate and adaptive immunity. Unlike αβ T-cells, γδ T-cells are not restricted by major histocompatibility complex (MHC) molecules, allowing them to respond rapidly to stress signals, pathogens, and tissue damage in an innate-like manner. They can be broadly classified into several subtypes based on their γδ TCR repertoire, tissue localization, and functional attributes. In humans, these subsets are defined by their expression of the δ chain (Vδ1, Vδ2, and Vδ3), whereas γδ T-cell subsets in mice are characterized by the expression of the γ chain (Vγ1, Vγ4, Vγ5, Vγ6, and Vγ7) (Hu et al., 2023b, Ribot et al., 2021).

γδ T-cells are present at low frequencies in peripheral blood (PB) and lymphoid tissues but are strategically enriched in various tissues, including the intestinal mucosa, where they form a predominant subpopulation. These cells contribute to tissue homeostasis and immune defense against stressed cells and pathogens (Kabelitz, 2023, Li et al., 2023, Rampoldi and Prinz, 2022). Thus, according to their tissue localization, Vδ1 and Vδ3 cells are found mainly in the gut, skin, and liver, while Vδ2 cells are localized in PB. Similarly, mouse Vγ5, Vγ6, and Vγ7 cells are tissue-resident, while Vγ1 and Vγ4 cells migrate from tissue to lymphatic nodes.

Within the intestinal environment, γδ T-cells exhibit diverse phenotypic and functional characteristics. The functional diversity of intestinal γδ T-cells is crucial for maintaining intestinal health. Notably, intestinal γδ T-cells are predominantly found within the intraepithelial lymphocyte (IEL) compartment, referred to as γδ IELs, whose primary function is to maintain the integrity of the intestinal barrier. Additionally, in the lamina propria (LP), they are referred to as LP lymphocytes, playing key roles in a range of immunological processes, including cytokine production. In this context, γδ T-cells can be classified as interferon (IFN)γ-producing γδ T (γδT1) and IL-17-producing γδ T-cells (γδT17), although γδ cells can produce a variety of other cytokines. Moreover, γδ T-cells can induce cytotoxic responses, contributing to the recognition and elimination of infected or transformed cells, thereby preventing infections and tumor development (Li et al., 2023).

In the intestinal environment, γδ T-cells specific to Peyer´s patches exhibit antigen presentation functions. For instance, a specific subset of human γδ T-cells, Vδ2 T-cells, serves as professional antigen-presenting cells (Hu et al., 2023b). Therefore, γδ T-cells from Peyer´s patches play a role in the humoral immunity of this area (Rampoldi & Prinz, 2022). Depending on the environment, this dual capacity underscores the significance of γδ T-cells in both the development and prevention of intestinal diseases (Fig. 1).

APC: antigen-presenting cells; γδT1: IFNγ-producing γδ T; γδT17: IL-17-producing γδ T-cells; IEL: Intraepithelial lymphocyte; KGF-1: Keratinocyte growth factor 1; LPLs: Lamina propria lymphocytes; TNF: Tumor necrosis factor.